Histone deacetylase inhibitors induce mitotic slippage

Stevens, Frances, Beamish, Heather J., Robyn Warrener and Gabrielli, Brian G. (2008) Histone deacetylase inhibitors induce mitotic slippage. Oncogene, 27 10: 1345-1354. doi:10.1038/sj.onc.1210779


Author Stevens, Frances
Beamish, Heather J.
Robyn Warrener
Gabrielli, Brian G.
Title Histone deacetylase inhibitors induce mitotic slippage
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2008-02-28
Year available 2007
Sub-type Article (original research)
DOI 10.1038/sj.onc.1210779
Open Access Status
Volume 27
Issue 10
Start page 1345
End page 1354
Total pages 10
Place of publication The United Kingdom
Publisher Nature Pub. Group
Language eng
Subject C1
920102 Cancer and Related Disorders
060103 Cell Development, Proliferation and Death
Abstract Chromosomal passenger proteins have emerged as key players in the regulation of mitosis and cytokinesis. Histone deacetylase inhibitors (HDACi) are a class of anticancer drugs that induce aberrant mitosis and can overcome the spindle assembly checkpoint. Here, we investigate the mechanism by which HDACi disrupt normal mitotic progression and checkpoint function. We demonstrate that HDACi treatment temporarily delays mitotic progression through prometaphase due to activation of the spindle assembly checkpoint. Despite failing to congress chromosomes to the metaphase plate, cells aberrantly segregate their chromosomes and exit mitosis to undergo a failed cytokinesis. We show that this premature exit from mitosis is a form of mitotic slippage. Chromosomal passenger proteins fail to accumulate at the centromere following HDACi treatment. This results in inadequate concentrations of chromosomal passenger proteins at the centromere, which are insufficient to regulate the phosphorylation of the kinetochore checkpoint component BubR1, and an inability to maintain the mitotic arrest. Thus, the centromeric accumulation of chromosomal passenger complex components is critical for regulating kinetochore but not centromeric processes, and failure of this accumulation underlies the HDACi-induced mitotic slippage.
Keyword HDACi
centromere
mitosis
aurora B
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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Created: Tue, 24 Mar 2009, 22:49:23 EST by Kylie Hengst on behalf of UQ Diamantina Institute